Journal of Antimicrobial Chemotherapy最新文献

{"title":"Population pharmacokinetics of aciclovir and its major metabolite 9-carboxymethoxymethylguanine and safety profile of valaciclovir in early liver transplant recipients.","authors":"Benjamin Kably, Mathilde Briard, Claire Francoz, Olivier Roux, Nadhira Houhou, Vincent Mackiewicz, Gilles Peytavin, Francois Durand, Minh P Lê","doi":"10.1093/jac/dkaf070","DOIUrl":"https://doi.org/10.1093/jac/dkaf070","url":null,"abstract":"<p><strong>Background: </strong>Valaciclovir is frequently prescribed for cytomegalovirus infection prophylaxis. Its major metabolite 9-carboxymethoxymethylguanine (9-CMMG), when accumulated in renally impaired patients, is neurotoxic. Its synthesis involves enzymes that could be impacted in liver transplant recipients. This retrospective study aimed to describe the pharmacokinetic (PK) and safety profile of aciclovir and 9-CMMG early after liver transplantation in patients receiving valaciclovir prophylaxis.</p><p><strong>Methods: </strong>Consecutive (ideally five) blood samples were drawn. Plasma concentrations of aciclovir/9-CMMG were quantified by UPLC-MS/MS. Medical data were collected from digital records. A joint population PK model for aciclovir/9-CMMG was developed (Monolix 2023R1). Monte Carlo simulations were used to estimate Cmin and AUC0-24.</p><p><strong>Results: </strong>Fifty patients (21 women) in the postoperative phase of liver transplantation were enrolled, with median age of 56.0 years and median weight of 69.5 kg; 255 samples were collected 19.0 days after transplantation. No drug-drug interaction was reported. A one-compartment model with first-order absorption best described the pharmacokinetics (PK). Covariate analysis showed that aciclovir and 9-CMMG clearances correlated with estimated glomerular filtration rate (eGFR). In normorenal patients, receiving valaciclovir 2000 mg q8h, estimated AUC0-24 values were 44.8 and 13.3 mg·h/L for aciclovir and 9-CMMG, respectively. The median estimated metabolic ratio of AUC0-24 (9-CMMG/aciclovir) was 30.4% and 129.9% for patients with >90 and <30 mL/min/1.73 m2 eGFR, respectively. There were no valaciclovir-related adverse events during hospitalization.</p><p><strong>Conclusions: </strong>This model allowed the PK and basal metabolic ratio of aciclovir and 9-CMMG in early liver transplantation to be defined. The correlation with renal function suggests important implications for therapeutic drug monitoring of these compounds, which will need confirmation in different cohorts.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics and exposure-response relationship of the antituberculosis drug BTZ-043.","authors":"Simon E Koele, Norbert Heinrich, Veronique R De Jager, Julia Dreisbach, Patrick P J Phillips, Petra Gross-Demel, Rodney Dawson, Kim Narunsky, Leticia M Wildner, Timothy D Mchugh, Lindsey H M Te Brake, Andreas H Diacon, Rob E Aarnoutse, Michael Hoelscher, Elin M Svensson","doi":"10.1093/jac/dkaf076","DOIUrl":"https://doi.org/10.1093/jac/dkaf076","url":null,"abstract":"<p><strong>Introduction: </strong>BTZ-043 is a first-in-class benzothiazinone for the treatment of TB with demonstrated early bactericidal activity. BTZ-043 is metabolized into two major metabolites: M1 and M2. The aim of this study was to characterize the pharmacokinetics (PK) and early exposure-response (pharmacokinetic/pharmacodynamic, PK/PD) relationship for BTZ-043.</p><p><strong>Methods: </strong>A population PK/PD model for BTZ-043 and its metabolites was developed using data from a sequential Phase 1b/2a, randomized, controlled clinical trial in participants with pulmonary TB. BTZ-043 was administered in daily doses ranging from 250 to 1750 mg over 14 days. The decrease in bacterial load was determined by culture of sputum samples to quantify cfu on solid medium, and time to positivity in liquid medium.</p><p><strong>Results: </strong>In total, 77 participants received the experimental treatment. PK were best described by two-compartment disposition models for BTZ-043 and M2, and a one-compartment disposition model for M1. When given without food, the bioavailability was 54% (95% CI: 43%-65%) lower than with food. The decrease in bacterial load was described by a bilinear model with estimated node at 48 h. Participants in the highest dose group in Stage 2 (1000 mg) had a 2-fold faster decrease in mycobacterial load during the initial 2 days compared with participants in the lowest dose group (250 mg), driven by an Emax relationship to the BTZ-043total exposure (BTZ-043 + M2).</p><p><strong>Conclusions: </strong>We characterized the population PK/PD of BTZ-043 in trial participants with pulmonary TB. An exposure-response relationship was only apparent for the first 2 days on treatment, indicating the need for further dose-finding studies.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adequate posology of antimicrobial therapy in the septic critically ill in continuous veno-venous hemofiltration: a single centre prospective observational study.","authors":"Alberto Corona, Alice Veronese, Silvia Santini, Clemente Santorsola, Dario Cattaneo, Miryam Shuman","doi":"10.1093/jac/dkaf089","DOIUrl":"https://doi.org/10.1093/jac/dkaf089","url":null,"abstract":"<p><strong>Background: </strong>Determining the optimal antibiotic (ATB) dosage in septic critically ill patients on continuous renal replacement therapy (CRRT) is still challenging. CRRT further disrupts antibiotic PK, already altered by sepsis-induced fluid shifts, volume of distribution (VD) changes and half-life modifications.</p><p><strong>Materials and methods: </strong>Our multi-disciplinary team-comprising an intensivist, nephrologist and clinical pharmacologist-conducted a prospective observational cohort study to evaluate the extent of ATB removal by CRRT and to assess the pharmacokinetic/pharmacodynamic (PK/PD) parameters of the most commonly used antibiotics for treating severe infections.</p><p><strong>Results: </strong>A total of 135 ATB therapeutic drug monitoring (TDM) assessments were conducted, measuring total drug concentrations (C) in both plasma (P) and ultrafiltrate in 85 septic patients undergoing CRRT. A high sieving coefficient (∼75%) was recorded for all antibiotics, with CRRT-related drug loss described by the following equations: (i) [CUF-ATB](trough level) = 0.77 × [CP-ATB](trough level) + 0.93 ng/mL; (ii) [CUF-ATB](peak) = 0.77 × [CP-ATB](peak) + 3.1 ng/mL. The VD exhibited wide variability, with values exceeding those reported in the literature. Lower ATB molecular weight and steric hindrance were associated with a higher elimination rate constant (Kemin⁻¹). ATB TDM consistently correlated with AUC and AUC/MIC, ensuring effective bactericidal activity.</p><p><strong>Conclusions: </strong>Despite its limitations, our study suggests to carry out a loading dose for the main antibiotics and consider the daily drug loss, as identified by the linear regression equation, along with daily TDM to guide further dosing adjustments.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative performance of humanized plasma and epithelial lining fluid exposures of meropenem, cefiderocol and tobramycin against a challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa in a standardized neutropenic murine pneumonia model.","authors":"Andrew J Fratoni, Alissa M Padgett, Erin M Duffy, David P Nicolau","doi":"10.1093/jac/dkaf100","DOIUrl":"https://doi.org/10.1093/jac/dkaf100","url":null,"abstract":"<p><strong>Background: </strong>The COMBINE murine neutropenic pneumonia model looks to standardize an important element of preclinical development and provide interlaboratory uniformity. Herein we provide quantitative bacterial density in lung benchmark efficacy data of humanized exposures of meropenem, cefiderocol and tobramycin in plasma and epithelial lining fluid (ELF) against a collection of Klebsiella pneumoniae and Pseudomonas aeruginosa.</p><p><strong>Methods: </strong>In accordance with the COMBINE protocol, human-simulated regimens (HSRs) based on both plasma and ELF exposures of meropenem, cefiderocol (both as 2 g q8h as 3 h infusions) and tobramycin 7 mg/kg as 30 min infusions were tested against K. pneumoniae and P. aeruginosa isolates. The 24 h change in cfu/lung for each HSR was calculated. Each isolate was tested in duplicate against both the plasma and ELF HSRs on separate experiment days.</p><p><strong>Results: </strong>Meropenem HSRs demonstrated >1 log10 kill against all P. aeruginosa isolates with MICs of ≤16 mg/L, but only against K. pneumoniae isolates with MICs of ≤2 mg/L as isolates with MICs of >2 mg/L generally harboured carbapenemases. Cefiderocol HSRs uniformly achieved >1 log10 kill against both species at MICs of ≤8 mg/L, with net growth and extensive variability in P. aeruginosa isolates with MICs of 16 mg/L. All tobramycin-susceptible isolates demonstrated >1 log10 kill, while non-susceptible isolates did not. Differences in cfu/lung magnitude between the plasma and ELF HSRs were most pronounced around the clinical breakpoints.</p><p><strong>Conclusions: </strong>In the COMBINE pneumonia model, administration of plasma and ELF HSRs of meropenem, cefiderocol and tobramycin demonstrated 24 h cfu/lung within reason of expectation given known PK/PD properties and existing clinical breakpoints.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetic model of oral minocycline in critically ill adult patients with ventilator-associated pneumonia.","authors":"Zoe Athanassa, Paraskevi Papakyriakopoulou, Silvia Marquez Megias, Elmina-Marina Saitani, Sofia Manioudaki, Katerina Dimoula, Irina Petsa, Georgia Valsami, Aikaterini Sakagianni, Vassiliki Koumaki, Aristides Dokoumetzidis, Athanassios Tsakris","doi":"10.1093/jac/dkaf090","DOIUrl":"https://doi.org/10.1093/jac/dkaf090","url":null,"abstract":"<p><strong>Objectives: </strong>Multidrug-resistant Acinetobacter baumannii (MDR-A. baumannii) has become an emerging pathogen, causing ventilator-associated pneumonia (VAP), with limited treatment options available. MIN has re-emerged as a potential treatment option for MDR pathogens. However, evidence regarding MIN pharmacokinetic properties in critically ill patients is scarce and primarily limited to IV administration. To address the knowledge gap in regions where IV MIN is unavailable, a prospective, open-label study was conducted to describe the pharmacokinetic properties of orally administered MIN.</p><p><strong>Methods: </strong>The study included 24 critically ill patients with MDR-A. baumannii VAP. A population PK (popPK) model was developed and the PTA for different MICs was assessed by Monte Carlo simulations. A one-compartment model with first-order absorption and linear elimination best described the data.</p><p><strong>Results: </strong>The values of the estimated population parameters were found equal to 183.3 L, 6.55 L/h and 1.66 h⁻¹, for the apparent volume of distribution (V/F), the apparent clearance (CL/F) and the absorption rate constant (ka), respectively (F representing oral bioavailability). PTA analysis showed that for a daily dose of 400 mg, adequate exposure [free AUC/MIC (fAUC/MIC > 25)] was achieved only for MICs ≤ 0.25 mg/L, while for the ratio of fAUC/MIC = 13.75, high PTA values are calculated up to MIC = 0.5 mg/L.</p><p><strong>Conclusions: </strong>This study provides a popPK model for oral MIN in critically ill adults. The developed popPK model contributes to a better understanding of MIN's PK and can inform dosing strategies and future studies on MIN use in critical care settings.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bactericidal activity of antibiotic combinations against clinical isolates of Enterococcus gallinarum and Enterococcus casseliflavus.","authors":"David Landman, Meir Cherniak, Orit Gefen, Ayelet Michael-Gayego, Yair Motro, Jacob Moran-Gilad, Jacob Strahilevitz","doi":"10.1093/jac/dkaf095","DOIUrl":"https://doi.org/10.1093/jac/dkaf095","url":null,"abstract":"<p><strong>Background: </strong>Enterococcus gallinarum and Enterococcus casseliflavus are increasingly identified as causes of healthcare-associated infections. Although hepatobiliary infection and catheter-related bloodstream infection predominate, endovascular infection can also occur. The optimal treatment of these infections is unknown.</p><p><strong>Objectives: </strong>To determine the in vitro activity of ampicillin, gentamicin and ceftriaxone against clinical isolates of E. gallinarum and E. casseliflavus.</p><p><strong>Methods: </strong>Bloodstream isolates of E. gallinarum (n = 10) and E. casseliflavus (n = 8) were collected from unique patients between 2008 and 2022 at one institution. The activity of ampicillin was tested alone and combined with gentamicin and ceftriaxone by the time-kill method.</p><p><strong>Results: </strong>All isolates were susceptible to ampicillin and none had gentamicin MIC > 128 mg/L. At concentrations of 0.25 × MIC, ampicillin plus gentamicin was synergistic against 5 of 10 E. gallinarum and all 8 E. casseliflavus, and was bactericidal against 12 of the 18 strains. In contrast, ampicillin plus ceftriaxone was synergistic and bactericidal against only 1 of 10 E. gallinarum and 0 of 8 E. casseliflavus. When the concentration of ampicillin was increased to 10 mg/L, above the MIC for all strains, the combination of ampicillin plus gentamicin was bactericidal against all isolates.</p><p><strong>Conclusions: </strong>These data suggest that the ampicillin plus gentamicin combination is frequently synergistic and typically bactericidal and may be the preferred treatment option for endovascular infection caused by E. gallinarum or E. casseliflavus. In contrast to the findings for Enterococcus faecalis, ampicillin plus ceftriaxone is generally not synergistic or bactericidal and thus may not be as effective.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biannual azithromycin mass drug administration for reduction of childhood mortality: a systematic review and meta-analysis.","authors":"Meenalotchini Prakash Gurunthalingam, Madhusudan Prasad Singh, Nitin Rewaram Gaikwad","doi":"10.1093/jac/dkaf092","DOIUrl":"https://doi.org/10.1093/jac/dkaf092","url":null,"abstract":"<p><strong>Background: </strong>Biannual mass drug administration of azithromycin (MDA-azithromycin) has been proposed as a strategy to reduce childhood mortality in high-mortality regions, particularly sub-Saharan Africa. However, its effectiveness across different age groups and potential risks, including antibiotic resistance, require further evaluation.</p><p><strong>Methods: </strong>We systematically searched PubMed, Cochrane CENTRAL, Web of Science and ClinicalTrials.gov through September 2024 for randomized controlled trials (RCTs) comparing biannual MDA-azithromycin to placebo in children aged 1-59 months. The primary outcomes were mortality in children <1 year and 12-59 months. Secondary outcomes included adverse events and antibiotic resistance. Data were analysed using a random-effects model in Review Manager 5.4, with heterogeneity assessed via I2. Trial sequential analysis (TSA) evaluated cumulative evidence reliability, and the Cochrane RoB2 tool assessed risk of bias. PROSPERO registration: CRD42024589170.</p><p><strong>Results: </strong>Five RCTs (691 235 children) were included. Among children <1 year, azithromycin showed a non-significant mortality reduction (RR: 0.90 [0.78, 1.04]; P = 0.14; I2 = 55%), with TSA indicating inconclusive evidence. Among children 12-59 months, MDA-azithromycin significantly reduced mortality (RR: 0.85 [0.79, 0.91]; P < 0.00001; I2 = 26%), with TSA confirming sufficient evidence. Adverse events were rare, but antibiotic resistance data were limited, warranting further monitoring. Evidence quality ranged from moderate to very low, with one trial at high risk of bias.</p><p><strong>Conclusion: </strong>Biannual MDA-azithromycin significantly reduces mortality in children 12-59 months, supporting its use in high-mortality settings per WHO recommendations. Its impact on infants remains uncertain. Adverse events were minimal, but continued resistance surveillance is essential.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing serotype coverage of pneumococcal vaccines with PCV21 (V116), a new 21-valent conjugate pneumococcal vaccine, and the epidemiology of its eight unique Streptococcus pneumoniae serotypes (15A, 15C, 16F, 23A, 23B, 24F, 31 and 35B) causing invasive pneumococcal disease in adult patients in Canada: SAVE study, 2018-21.","authors":"John J Schellenberg, Heather J Adam, Melanie R Baxter, James A Karlowsky, Alyssa R Golden, Irene Martin, George G Zhanel","doi":"10.1093/jac/dkaf085","DOIUrl":"https://doi.org/10.1093/jac/dkaf085","url":null,"abstract":"<p><strong>Background: </strong>V116 is a novel 21-valent pneumococcal conjugate vaccine (PCV) intended for use in adults.</p><p><strong>Objectives: </strong>To estimate current V116 serotype coverage in adult patients in Canada compared with PCV15, PCV20 and PPSV23 vaccines, and to describe isolate demographics for the eight unique serotypes (15A, 15C, 16F, 23A, 23B, 24F, 31 and 35B) covered by V116.</p><p><strong>Methods: </strong>From 2018 to 2021 inclusive, the SAVE study collected 5854 invasive pneumococcal disease (IPD) isolates as part of a collaboration between the Canadian Antimicrobial Resistance Alliance and the Public Health Agency of Canada-National Microbiology Laboratory. Serotypes were determined by Quellung reaction and antimicrobial susceptibility testing performed using the CLSI broth microdilution method.</p><p><strong>Results: </strong>For adult patients (≥18 years), adults 50-64 years and adults ≥65 years, respectively, IPD isolate coverage was PCV15 (42.7%; 41.0%, 39.8%), PCV20 (59.0%; 60.2%, 52.2%), PPSV23 (70.4%; 75.1%, 60.0%), V116 (78.9%; 76.3%, 81.5%) and V116 plus PCV20 (92.2%; 91.0%, 89.3%). The eight unique V116 serotypes accounted for 19.7% and 26.8% of IPD isolates from adults and adults ≥65 years, respectively. Among the eight unique V116 serotypes, 15A and 23A demonstrated the highest rates of MDR (17.0% and 10.2%, respectively); 6.7% of 15A isolates were XDR.</p><p><strong>Conclusions: </strong>V116 provided significantly (P < 0.05) greater coverage than PCV15, PCV20 and PPSV23 for adults, including older adults, across all Canadian geographic regions, and against IPD isolates with common antimicrobial resistance phenotypes, including MDR. The eight unique V116 serotypes accounted for a higher proportion of IPD isolate serotypes in patients aged ≥65 years than younger adults.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pre-post quasi-experimental study of the impact of TDM-guided aggressive pharmacokinetic/pharmacodynamic target attainment of continuous infusion ceftolozane/tazobactam monotherapy in treating severe Pseudomonas aeruginosa infections: a strategy useful for raising the bar?","authors":"Milo Gatti, Matteo Rinaldi, Cecilia Bonazzetti, Antonio Siniscalchi, Tommaso Tonetti, Simone Ambretti, Maddalena Giannella, Pierluigi Viale, Federico Pea","doi":"10.1093/jac/dkaf098","DOIUrl":"https://doi.org/10.1093/jac/dkaf098","url":null,"abstract":"<p><strong>Objectives: </strong>To assess the clinical usefulness of a therapeutic drug monitoring (TDM)-guided strategy for attaining an aggressive pharmacokinetic/pharmacodynamic (PK/PD) target of continuous infusion (CI) ceftolozane/tazobactam monotherapy in patients having Pseudomonas aeruginosa infections.</p><p><strong>Methods: </strong>We performed a pre-post quasi-experimental study including adult patients with documented P. aeruginosa bacteraemia and/or pneumonia who were treated with CI ceftolozane/tazobactam monotherapy tailored by means of a TDM-guided strategy in the period 1 November 2023 to 31 July 2024 (post-intervention phase) compared with patients receiving standard management with CI ceftolozane/tazobactam monotherapy in the period 1 April 2022 to 31 October 2023 (pre-intervention phase). Clinical outcomes were compared between pre- and post-intervention phase. Univariate and multivariate analyses were performed for identifying variables associated with microbiological failure.</p><p><strong>Results: </strong>Eighty-five patients (48 in pre- and 37 in post-intervention phase) were included. Demographics and clinical features were similar in both groups. No significant difference emerged between groups in terms of microbiological eradication (P = 0.10), 30 day resistance to ceftolozane/tazobactam (P = 0.37), clinical cure (P = 0.26) and 30 day mortality rate (P = 0.79). All patients in the post-intervention phase attained an optimal PK/PD target, allowing the use of a lower ceftolozane/tazobactam CI daily dosing regimen compared with the pre-intervention phase (3.0 g/1.5 g versus 6.0 g/3.0 g; P = 0.06). The only independent predictors of microbiological failure were difficult-to-treat resistant P. aeruginosa isolates in the pre-intervention group (OR 6.99; 95% CI 1.34-36.55), and a ratio of partial pressure of arterial oxygen to fraction of oxygen in the inhaled air (Pao2/Fio2 ratio) <200 in the post-intervention group (OR 18.00; 95% CI 1.86-174.22).</p><p><strong>Conclusions: </strong>Our TDM-guided strategy of CI ceftolozane/tazobactam was cost-effective in attaining an aggressive PK/PD target of ceftolozane against susceptible P. aeruginosa strains with lower than standard daily doses without compromising efficacy.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nature-inspired designing of KLR- and KLS-rich antimicrobial peptides: unleashing the antibiofilm potential of RbP12 against MDR S. aureus and P. aeruginosa.","authors":"Zeeshan Yaseen, Saiqa Aslam, Sidra Rahmat Ullah, Abdur Rahman, Muhammad Bilal Khan Niazi, Saadia Andleeb","doi":"10.1093/jac/dkaf079","DOIUrl":"https://doi.org/10.1093/jac/dkaf079","url":null,"abstract":"<p><strong>Objectives: </strong>Biofilm formation is a mechanism exhibited by bacteria, making them 10-1000 times more resistant than planktonic cells. The aim was to collect the most suitable characteristics from already available antibiofilm peptides and design novel antibiofilm peptide sequences along with these characteristics altogether in one sequence.</p><p><strong>Methods: </strong>Antibiofilm peptides were collected from AMP database (APD3), and sequence analysis was performed to derive the most suitable features. An artificial design approach, modified database filtering technology, was chosen to design novel peptide sequences, and their activity was predicted by machine-learning prediction models. Antibacterial and antibiofilm potential of the selected peptide sequence (arginine-based peptide 12; RbP12) was assessed against Staphylococcus aureus P10 and Pseudomonas aeruginosa PA64.</p><p><strong>Results: </strong>A total of 34 peptides were designed, of which 22 were arginine based and 12 were serine based. All the designed peptides were predicted to have antibiofilm properties. RbP12 was found to inhibit the growth of S. aureus P10 completely at an MIC of 85 mg/L, while the percentage inhibition of P. aeruginosa PA64 was calculated to be 32.1%. Significant inhibition of biofilms by RbP12 was observed in the case of both S. aureus P10 and P. aeruginosa PA64. An MTT assay showed no significant cytotoxicity by RbP12 with 96% cell viability.</p><p><strong>Conclusions: </strong>RbP12 was found to have higher antibacterial and antibiofilm activity against S. aureus P10 compared with P. aeruginosa PA64. With 96% cell viability, usage of RbP12 on human skin is totally safe. Based on these results, the aim is to develop self-assembled peptide hydrogels for wound healing in future work.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}